The interest in platinum-based antitumor drugs has its origin in the 1960's, with the serendipitous discovery by Rosenberg of the inhibition of cell division by platinum (Pt) complexes. Since the approval of cisplatin for the treatment of testicular and ovarian cancer in 1978, cisplatin has become one of the three most widely utilized antitumor drugs in the world. Platinum-based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use, especially for management of tumors of the ovary, testes, and the head and neck. Thousands of Pt compounds have been synthesized and evaluated as potential antitumor agents and over 28 have entered human clinical trials. However, several types of dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and other challenges have severely limited the patient quality of life. Therefore, it is desirable to develop new strategies for improving platinum therapy.
The search continues for an improved Pt antitumor agent. In the years following the introduction of cisplatin, the design of new Pt antitumor drugs focused mainly on direct cisplatin analogues, which adhered to the set of structure-activity relationships summarized by Cleare and Hoeschele in 1973. A number of researchers have taken a completely different approach to Pt drug design and have produced compounds that are inconsistent with the traditional structure-activity relationships but still show antitumor activities.
Carboplatin, one of the second generation platin analogues, is less toxic than cisplatin and can be administered at a significantly higher dose than cisplatin (up to 2000 mg/dose); it has received worldwide approval and has achieved routine clinical use. Unfortunately, the continued use of carboplatin is restricted by severe dose limiting side effects and intrinsic or acquired drug resistance.
In contrast to the 1970s and 1980s, the design of third-generation Pt drugs in the recent years has clearly shifted away from the early empirical structure-activity relationships and the synthesis of mere cisplatin analogues. Instead, efforts have been directed at the design of compounds capable of circumventing specific mechanisms of resistance and at the design of unconventional Pt compounds with radically different modes of action. As the third-generation of compounds undergo clinical trials, it is hoped that they will demonstrate significant clinical advantages over the current drugs, particularly in the area of Pt drug resistance.
Meanwhile co-crystallization has attracted great amount of academic, industrial and therapeutic interests by co-crystallization of two or more pure compounds with crystal engineering to create a new functional material. Specifically, pharmaceutical co-crystals are defined as “co-crystals in which the target molecule or ion is an active pharmaceutical ingredient, API, and it bonds to the co-crystal former(s) through hydrogen bonds.” Almarsson M. and Zaworotko J., Chem. Commun., 2004: 1889. Pharmaceutical co-crystals are nonionic supramolecular complexes and can be used to improve physiochemical properties such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the active pharmaceutical ingredient (API).
Therefore, it is desirable to improve the physiochemical and therapeutic properties of cisplatin, carboplatin and other platin with co-crystallization technology. In some cases, there is no need to change the basic structure of the platin as the API, while properties such as solubility, stability, permeability and bioavailability can be improved. For example, it would be possible to significantly enhance the bioavailability of a platin API with co-crystallization, so that the co-crystal can be therapeutically effective in certain environment of use and maintain the level for a prolonged period of time.
The present invention provides a series of co-crystals including a platinum analogue and a diacid as coformers. The co-crystals of this invention may satisfy one or more of the targeted objectives, such as but not limited to increased solubility, stability and bioavailability and more versatility in pharmaceutical use.